Since the accidental discovery of its biological properties over 40 years ago, cisplatin has made a major impact in the chemotherapeutic treatment of testicular and ovarian cancers and is still widely used today.
The initial driver for further platinum-drug development was the discovery of the severe safety issues that are raised with cisplatin, especially nephrotoxicity. This resulted in the development of carboplatin, which is, broadly speaking, equally effective to cisplatin, but with a more acceptable side-effect profile.
The mechanism of action of cisplatin (and carboplatin) involves covalent binding to purine DNA bases, which primarily leads to cellular apoptosis.
Much is now understood as to how tumours all too commonly exhibit resistance to cisplatin, either intrinsically or as acquired during courses of therapy. Major mechanisms include: decreased membrane transport of the drug, increased cytoplasmic detoxification, increased DNA repair, and increased tolerance to DNA damage.
The second driver for new platinum-drug development was to circumvent mechanisms of resistance, and thereby broaden the clinical utility of this class of agents. These efforts have resulted in oxaliplatin (active in patients with colorectal cancer), satraplatin (the first orally administered platinum drug, which shows promise in patients with prostate cancer) and picoplatin.
Improved delivery of platinum drugs to tumours is being studied in early clinical trials using liposomal-based or co-polymer-based products, as well as by the use of localized, intraperitoneal administration of cisplatin or carboplatin in patients with ovarian cancer.
It might also be possible to circumvent platinum-drug resistance in the clinic through modulating resistance mechanisms; for example, those involving increased glutathione or loss of DNA mismatch repair.
The accidental discovery of the anticancer properties of cisplatin and its clinical introduction in the 1970s represent a major landmark in the history of successful anticancer drugs. Although carboplatin — a second-generation analogue that is safer but shows a similar spectrum of activity to cisplatin — was introduced in the 1980s, the pace of further improvements slowed for many years. However, in the past several years interest in platinum drugs has increased. Key developments include the elucidation of mechanisms of tumour resistance to these drugs, the introduction of new platinum-based agents (oxaliplatin, satraplatin and picoplatin), and clinical combination studies using platinum drugs with resistance modulators or new molecularly targeted drugs.
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The author wishes to thank K. Harrap and members of his laboratory, from 1987 to 1997. Studies on what became satraplatin and picoplatin during this period were supported by what is now Cancer Research UK.
Lloyd Kelland received academic rewards as an employee of the Institute of Cancer Research (UK) from 1984 to 2001, with respect to the inventions of satraplatin and picoplatin.
A chemical reaction in which water molecules are incorporated into a compound; in the case of cisplatin, with either displacement of one chlorine (monoaqua species) or both chlorines (diaqua species).
- 'Leaving' groups
During its reaction with DNA the dichloro groups of cisplatin are displaced or substituted but the two ammine groups remain intact, leading to a convention to refer to the groups within platinum cancer drugs that are displaced as 'leaving groups' (and those that remain as stable or carrier ligands).
The process of administering large amounts of water (or fluid) to patients before chemotherapy.
A decreased bone-marrow function that results in lower numbers of red blood cells, white blood cells and platelets.
A decrease in the number of platelets in the blood.
- Carrier ligand
Stable groups on platinum drugs that are not replaced by substitution reactions.
- Objective response rate
The proportion of patients with defined tumour shrinkage; generally the sum of partial responses plus complete responses.
- Hazard ratio
The relative risk of experiencing a particular event; an HR of 0.6 means that one group has a 40% lower risk than the other group.
An oncogene belonging to the EGFR family that has an important role in around a quarter of all breast cancers.
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Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer 7, 573–584 (2007). https://doi.org/10.1038/nrc2167
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